Gastrointestinal Stromal Tumors (GISTs)

Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract. They start in special cells called the interstitial cells of Cajal (ICCs). ICCs are part of the autonomic nervous system and coordinate the automatic movements of the GI tract. ICCs are sometimes called the "pacemakers" of the GI tract because they send signals to the muscles of the digestive system, telling them to move food and liquid through the GI tract.

GISTs may occur anywhere along the length of the digestive tract from the esophagus to the anus.

Statistics

Although the exact incidence is still somewhat unclear, the American Cancer Society (ACS) estimates that each year between 4,000 and 5,000 Americans develop GISTs. It is slightly more common in men. Although GISTs are most often diagnosed in people ages 50 or older, they can occur in any age group. GIST appears to occur with increased frequency in people with a history of neurofibromatosis type 1 (NF1 disease, also known as von Recklinghausen disease).

About 60 percent of all GISTs develop in the stomach, while around 30 percent will arise in the small intestine, the ACS says. The rest arise in the esophagus, colon, and rectum.

Risk factors

The most substantial risk factor for GIST is the presence of neurofibromatosis. There are rare instances of familial GIST where several family members have the condition.

Screening

Unfortunately there is no general screening test to check for GISTs. However, the earlier any tumor is discovered and treated, the better the chance of survival. For this reason, people who notice signs or symptoms of GIST should discuss this with their doctor right away.

Symptoms

People with early stage GIST often don't have any symptoms of the disease. Most GISTs are diagnosed after a person develops symptoms. These may include:

Abdominal discomfort or pain

Vomiting

Blood in stools or vomit

Fatigue due to anemia (low blood counts)

Feeling full after eating only a small amount (early satiety)

Loss of appetite or weight loss

These symptoms may be the result of GIST or of other less serious causes. A person with these symptoms should discuss them with their doctor.

Why does GIST develop?

Scientists are beginning to unravel some of the processes that go on inside cells that cause them to develop into GISTs. Normally these cells, like other cells in the body, grow and divide in a controlled fashion. But sometimes things can go wrong, allowing these cells to grow out of control and ultimately become cancerous.

Scientists have discovered that cells may grow in an uncontrolled manner as the result of an abnormality in their DNA. In most GISTs, a specific mutation causes a cellular enzyme known as KIT to be switched "on" all the time. KIT is an enzyme (called a "tyrosine kinase") responsible for sending growth and survival signals inside the cell. If it is ON, the cell stays alive and grows or proliferates. The overactive, uncontrolled mutant KIT enzyme triggers the runaway growth of GIST cells. Much less often, GIST cells make too much of a different protein, called PDGFRA, which can also cause the cells to grow. This insight into the way GISTs develop has already helped to identify new treatments.

How is GIST diagnosed?

If a person feels a lump or experiences symptoms that may indicate the presence of a GIST, he or she should discuss them with a doctor. The doctor will take a detailed history of the patient and ask questions about the symptoms.

After a careful physical exam the doctor may perform tests such as endoscopy, X-ray tests, CT scan, or MRI to gain more information about whether there is an abnormal growth, where the growth is located, and whether it has spread.

In some cases a tissue sample, called a biopsy, may be needed. A doctor might perform one of three types of biopsies: fine needle aspiration; core needle biopsy; and excisional or incisional biopsy.

After the biopsy is taken, the sample is examined under a microscope by a pathologist. One of the things the pathologist will look for is whether there are detectable amounts of the KIT enzyme. KIT can be identified by looking for a portion of the enzyme called the "CD117" antigen (this is a bit of the enzyme that can be detected by a special diagnostic test). Most GISTs produce KIT, and detection of CD117 (called "expression of CD117" or "CD117 positivity") helps prove that the growth is a GIST. If CD117 is not detected, the sample may be tested for the PDGFRA protein.

Once a GIST has been identified, it is important to determine the best way to treat it. Ideally, surgery should be considered, to be performed by an expert surgeon who has experience in GIST management. GISTs grow differently in each patient. The size of the tumor and the rate at which they grow are important in determining the risk the tumor presents. Specifically, the risk of spread to other parts of the body (a process called metastasis) can vary greatly, with some very small GISTs essentially never spreading, whereas larger GISTs virtually always spread.

Distinguishing benign from malignant tumors can be difficult. It is important to recognize that current consensus notes all GISTs as being at some risk of malignant behavior. In some cases even small tumors that are not growing rapidly may spread or metastasize. The location of the tumor seems to affect the tumor's behavior. For example, a small GIST from the small intestine may grow more quickly and be more likely to spread than a large tumor from the stomach. When a GIST metastasizes it usually spreads to the liver or peritoneal cavity (the lining of the abdominal wall).

How is GIST is treated?

Conventional approaches

Until recently, the only treatment for GIST was surgery. The goal of surgery is to remove the tumor completely. However, surgery alone for larger GISTs, or for GISTs that have spread, yielded disappointing results.

Because there is a chance that malignant tumors can recur or come back after surgery, chemotherapy or radiation is used with many types of cancer. This is called adjuvant therapy. However, in the case of GIST, using either chemotherapy or radiation after surgery has not been shown to work in preventing the tumor from coming back. For this reason researchers have sought new effective therapies for GIST.

New treatments

A new drug has been shown to be effective in treating GIST. The drug, called Gleevec (imatinib), is used for patients with advanced-stage GIST, and it may also help patients with earlier-stage tumors, either before or after surgery. It doesn't seem to cure advanced GISTs, but it can help people with them live longer and feel better.

Most anticancer therapies developed in the past kill both tumor cells and normal cells, but Gleevec is able to disable the tumor cells while leaving most healthy cells unharmed. Gleevec blocks the overactive KIT and PDGFRA enzymes in the tumor cells. This disables the GIST cells so that many of them are destroyed.

By selectively killing tumor cells while allowing healthy cells to survive, Gleevec represents a new approach in cancer therapy called targeted therapy.

Gleevec is taken as an oral capsule and it is usually recommended that it be taken with a meal and a large glass of water to reduce irritation to the intestinal tract. Side effects of Gleevec are mostly mild to moderate. The most common side effect is mild nausea. Other side effects, usually mild as well, include diarrhea, fluid retention and swelling (often around the eyes), indigestion, muscle cramps, bleeding from the GIST tumor, fatigue, and a skin rash.

Sutent (sunitinib) is another targeted therapy drug that is useful in treating GIST. It targets the KIT and PDGFRA proteins and several other proteins that Gleevec does not target. It is used in patients when Gleevec doesn't work or if they can't take it because of side effects. It seems to help about one out of three patients who can't take Gleevec. Sutent can cause tumors to shrink and often stops them from growing for a time. More important, patients getting the drug may live longer.

Sutent is also taken as a pill. The most common side effects are diarrhea, mouth irritation, and skin color changes. More serious side effects can include high blood pressure, increased risk of bleeding, and swelling.